Colorectal cancer, susceptibility to, 12

Summary

Colorectal cancer, susceptibility to, 12 (MONDO:0014038) is a cancer caused by POLE (GenCC Strong), with 4 cohort genes (1 CIViC-evidence somatic driver; 1,082 ClinVar predisposition records).

At a glance

• Classification: Cancer
• Causal gene: POLE (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 1,082

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	colorectal cancer, susceptibility to, 12
Mondo ID	MONDO:0014038
OMIM	615083
UMLS	C3554460
MedGen	767374
GARD	0027855
Is cancer (heuristic)	yes

Also known as: colorectal cancer caused by mutation in POLE · colorectal cancer, susceptibility to, 12 · colorectal cancer, susceptibility to, type 12 · CRCS12 · POLE colorectal cancer

Data availability: 1,082 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary neoplastic syndrome › colorectal cancer, susceptibility to, 12

Related subtypes (116): mosaic variegated aneuploidy syndrome, tuberous sclerosis, hereditary breast ovarian cancer syndrome, hereditary multiple osteochondromas, nevoid basal cell carcinoma syndrome, leukemia, chronic lymphocytic, susceptibility to, 2, blue rubber bleb nevus, cherubism, Beckwith-Wiedemann syndrome, multiple self-healing squamous epithelioma, erythroleukemia, familial, susceptibility to, goiter, multinodular 1, with or without Sertoli-Leydig cell tumors, hyperparathyroidism 2 with jaw tumors, Kaposi sarcoma, susceptibility to, hereditary leiomyomatosis and renal cell cancer, susceptibility to uveal melanoma, melanoma and neural system tumor syndrome, nasopharyngeal carcinoma, susceptibility to, 2, WAGR syndrome, neuroblastoma, susceptibility to, 1, Rothmund-Thomson syndrome, mismatch repair cancer syndrome 1, Wiskott-Aldrich syndrome, N syndrome, hereditary thrombocytopenia and hematologic cancer predisposition syndrome, prostate cancer/brain cancer susceptibility, Brooke-Spiegler syndrome, pancreatic cancer, susceptibility to, 1, Carney-Stratakis syndrome, nasopharyngeal carcinoma, susceptibility to, 1, ovarian cancer, susceptibility to, 1, colorectal cancer, susceptibility to, 1, lung cancer susceptibility 1, leukemia, chronic lymphocytic, susceptibility to, 1, Kostmann syndrome, colorectal cancer, susceptibility to, 2, colorectal cancer, susceptibility to, 3, colorectal cancer, susceptibility to, 5, colorectal cancer, susceptibility to, 6, colorectal cancer, susceptibility to, 7, leukemia, chronic lymphocytic, susceptibility to, 3, leukemia, chronic lymphocytic, susceptibility to, 4, leukemia, chronic lymphocytic, susceptibility to, 5, lung cancer susceptibility 3, colorectal cancer, susceptibility to, 8, colorectal cancer, susceptibility to, 9, colorectal cancer, susceptibility to, 10, colorectal cancer, susceptibility to, 11, lung cancer susceptibility 4, neuroblastoma, susceptibility to, 3, neuroblastoma, susceptibility to, 4, neuroblastoma, susceptibility to, 5, neuroblastoma, susceptibility to, 6, leukemia, acute lymphocytic, susceptibility to, 1, leukemia, acute lymphocytic, susceptibility to, 2, lung cancer susceptibility 5, BAP1-related tumor predisposition syndrome, familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome, Maffucci syndrome, basal cell carcinoma, susceptibility to, 7, leukemia, acute lymphoblastic, susceptibility to, 3, cholangiocarcinoma, susceptibility to, progeroid features-hepatocellular carcinoma predisposition syndrome, neuroblastoma, susceptibility to, 7, DDX41-related hematologic malignancy predisposition syndrome, nasopharyngeal carcinoma, susceptibility to, 3, familial isolated hyperparathyroidism, intestinal polyposis syndrome, dyskeratosis congenita, familial rhabdoid tumor, multiple endocrine neoplasia, hereditary pheochromocytoma-paraganglioma, PTEN hamartoma tumor syndrome, familial multiple fibrofolliculoma, hereditary retinoblastoma, familial atypical multiple mole melanoma syndrome, hereditary nonpolyposis colon cancer, Li-Fraumeni syndrome, Cobb syndrome, neurofibromatosis, susceptibility to familial cutaneous melanoma, pancreatic cancer, susceptibility to, 5, leukemia, acute myeloid, susceptibility to, diffuse gastric and lobular breast cancer syndrome with or without cleft lip and/or palate, glioma susceptibility, hemangioma, capillary infantile, susceptibility to, CDH1-related diffuse gastric and lobular breast cancer syndrome, NTHL1-deficiency tumor predisposition syndrome, SAMD9-related spectrum and myeloid neoplasm risk, neuroblastoma, susceptibility to, 2, BARD1-related cancer predisposition, BRCA1-related cancer predisposition, BRCA2-related cancer predisposition, ATM-related cancer predisposition, CHEK2-related cancer predisposition, PALB2-related cancer predisposition, RAD51C-related cancer predisposition, RAD51D-related cancer predisposition, Li-fraumeni-like syndrome, breast cancer, familial, susceptibility to, 1, breast cancer, familial, susceptibility to, 2, breast cancer, familial, susceptibility to, 3, colorectal cancer, susceptibility to, 4, colorectal cancer, susceptibility to, on chromosome 15, ovarian cancer, familial, susceptibility to, 1, ovarian cancer, familial, susceptibility to, 2, ovarian cancer, familial, susceptibility to, 3, inherited hematologic cancer-predisposing syndrome, mosaic neurofibromatosis/schwannomatosis, tumor predisposition syndrome 2, prostate cancer, hereditary, X-linked 3, follicular lymphoma, susceptibility to, GPR161-related medulloblastoma predisposition, SAMD9L-related spectrum and myeloid neoplasm risk, HAVCR2-related cancer predisposition, EGLN1-related erythrocytosis and pheochromocytoma/paraganglioma predisposition

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

159 uncertain significance, 138 benign/likely benign, 122 conflicting classifications of pathogenicity, 120 likely benign, 48 benign, 7 likely pathogenic, 6 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1015503	NC_000012.11:g.(?133263830)(133263901_?)del	POLE	Pathogenic	criteria provided, single submitter
1450491	NC_000012.11:g.(?133252670)(133263901_?)del	POLE	Pathogenic	criteria provided, single submitter
1974108	NM_006231.4(POLE):c.1184_1188dup (p.Tyr397fs)	POLE	Pathogenic	criteria provided, single submitter
2582706	NM_006231.4(POLE):c.2154del (p.Lys717_Tyr718insTer)	POLE	Pathogenic	criteria provided, single submitter
2717088	NM_006231.4(POLE):c.5678+1G>T	POLE	Pathogenic	criteria provided, multiple submitters, no conflicts
40046	NM_006231.4(POLE):c.1270C>G (p.Leu424Val)	POLE	Pathogenic	criteria provided, multiple submitters, no conflicts
2179302	NM_006231.4(POLE):c.579-1G>C	POLE	Likely pathogenic	criteria provided, single submitter
2180430	NM_006231.4(POLE):c.2468+1G>T	POLE	Likely pathogenic	criteria provided, single submitter
2425543	NC_000012.11:g.(?133210752)(133210984_?)dup	POLE	Likely pathogenic	criteria provided, single submitter
2664946	NM_006231.4(POLE):c.2753C>A (p.Ser918Ter)	POLE	Likely pathogenic	criteria provided, single submitter
3391117	NM_006231.4(POLE):c.1372T>C (p.Tyr458His)	POLE	Likely pathogenic	criteria provided, single submitter
372061	NM_006231.4(POLE):c.3459+2T>C	POLE	Likely pathogenic	criteria provided, single submitter
4056102	NM_006231.4(POLE):c.3276-1G>A	POLE	Likely pathogenic	criteria provided, single submitter
218680	NM_006231.4(POLE):c.16G>C (p.Gly6Arg)	LOC130009266	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
246154	NM_006231.4(POLE):c.2T>C (p.Met1Thr)	LOC130009266	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
246298	NM_006231.4(POLE):c.-6G>A	LOC130009266	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
372020	NM_006231.4(POLE):c.2T>G (p.Met1Arg)	LOC130009266	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
405608	NM_006231.4(POLE):c.1A>G (p.Met1Val)	LOC130009266	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1020965	NM_006231.4(POLE):c.3339G>A (p.Trp1113Ter)	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1036273	NM_006231.4(POLE):c.5908T>C (p.Ser1970Pro)	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1050781	NM_006231.4(POLE):c.4375G>T (p.Glu1459Ter)	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1208579	NM_006231.4(POLE):c.910-13T>C	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1461993	NM_006231.4(POLE):c.3668C>T (p.Pro1223Leu)	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1508880	NM_006231.4(POLE):c.5333C>T (p.Ala1778Val)	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1697427	NM_006231.4(POLE):c.626A>G (p.Lys209Arg)	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1709984	NM_006231.4(POLE):c.1168del (p.Gln390fs)	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1729536	NM_006231.4(POLE):c.1135C>T (p.His379Tyr)	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1738116	NM_006231.4(POLE):c.4136C>T (p.Ala1379Val)	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1755247	NM_006231.4(POLE):c.6754A>C (p.Met2252Leu)	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
220705	NM_006231.4(POLE):c.2089C>A (p.Pro697Thr)	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 5 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
POLE	Act	ACC,BLCA	CIViC #4386

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
POLE	Definitive	Autosomal dominant	POLE-related polyposis and colorectal cancer syndrome	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
POLE	Orphanet:352712	Facial dysmorphism-immunodeficiency-livedo-short stature syndrome
POLE	Orphanet:440437	Familial colorectal cancer Type X
POLE	Orphanet:447877	Polymerase proofreading-related polyposis
POLE	Orphanet:85173	IMAGe syndrome
KBTBD13	Orphanet:171439	Childhood-onset nemaline myopathy

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
POLE	HGNC:9177	ENSG00000177084	Q07864	DNA polymerase epsilon catalytic subunit A	gencc,clinvar
DDX51	HGNC:20082	ENSG00000185163	Q8N8A6	ATP-dependent RNA helicase DDX51	clinvar
EXOC4	HGNC:30389	ENSG00000131558	Q96A65	Exocyst complex component 4	clinvar
KBTBD13	HGNC:37227	ENSG00000234438	C9JR72	Kelch repeat and BTB domain-containing protein 13	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
POLE	DNA polymerase epsilon catalytic subunit A	Catalytic component of the DNA polymerase epsilon complex.
DDX51	ATP-dependent RNA helicase DDX51	ATP-binding RNA helicase involved in the biogenesis of 60S ribosomal subunits.
EXOC4	Exocyst complex component 4	Component of the exocyst complex involved in the docking of exocytic vesicles with fusion sites on the plasma membrane.
KBTBD13	Kelch repeat and BTB domain-containing protein 13	Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 3 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Transcription factor	1	2.1×	0.404
Other/Unknown	3	1.3×	0.404

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
POLE	Transcription factor	no	2.7.7.7	DNA-dir_DNA_pol_B_exonuc, DNA-dir_DNA_pol_B, RNaseH-like_sf
DDX51	Other/Unknown	no		RNA-helicase_DEAD-box_CS, Helicase_C-like, DEAD/DEAH_box_helicase_dom
EXOC4	Other/Unknown	no		Sec8_exocyst_N, Sec8/EXOC4, Sec8_M
KBTBD13	Other/Unknown	no		BTB/POZ_dom, Kelch_1, SKP1/BTB/POZ_sf

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar hemisphere	2
right hemisphere of cerebellum	2
right testis	1
right frontal lobe	1
bone marrow cell	1
calcaneal tendon	1
cortical plate	1
hindlimb stylopod muscle	1
primordial germ cell in gonad	1
skeletal muscle tissue	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
POLE	221	ubiquitous	marker	right hemisphere of cerebellum, right testis, cerebellar hemisphere
DDX51	134	ubiquitous	yes	right hemisphere of cerebellum, right frontal lobe, cerebellar hemisphere
EXOC4	261	ubiquitous	marker	bone marrow cell, cortical plate, calcaneal tendon
KBTBD13	47	tissue_specific	yes	primordial germ cell in gonad, hindlimb stylopod muscle, skeletal muscle tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
POLE	3,267
DDX51	3,116
EXOC4	2,865
KBTBD13	606

Structural data

PDB: 2 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POLE	Q07864	18
EXOC4	Q96A65	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KBTBD13	C9JR72	90.56
DDX51	Q8N8A6	74.64

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 20. Enrichment computed across 4 evidence-associated genes (3 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
DNA replication initiation	1	475.8×	0.023	POLE
VxPx cargo-targeting to cilium	1	173.0×	0.023	EXOC4
PCNA-Dependent Long Patch Base Excision Repair	1	173.0×	0.023	POLE
Insulin processing	1	152.3×	0.023	EXOC4
Gap-filling DNA repair synthesis and ligation in GG-NER	1	146.4×	0.023	POLE
Recognition of DNA damage by PCNA-containing replication complex	1	126.9×	0.023	POLE
Termination of translesion DNA synthesis	1	115.3×	0.023	POLE
Activation of the pre-replicative complex	1	108.8×	0.023	POLE
Dual Incision in GG-NER	1	86.5×	0.026	POLE
HDR through Homologous Recombination (HRR)	1	63.4×	0.029	POLE
Gap-filling DNA repair synthesis and ligation in TC-NER	1	59.5×	0.029	POLE
Dual incision in TC-NER	1	57.7×	0.029	POLE
Translocation of SLC2A4 (GLUT4) to the plasma membrane	1	51.4×	0.030	EXOC4
Class I MHC mediated antigen processing & presentation	1	23.4×	0.060	KBTBD13
Neddylation	1	15.8×	0.083	KBTBD13
Antigen processing: Ubiquitination & Proteasome degradation	1	12.4×	0.098	KBTBD13
Adaptive Immune System	1	9.9×	0.114	KBTBD13
Post-translational protein modification	1	6.4×	0.165	KBTBD13
Immune System	1	4.3×	0.223	KBTBD13
Metabolism of proteins	1	4.1×	0.223	KBTBD13

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of the force of skeletal muscle contraction	1	1404.3×	0.006	KBTBD13
DNA replication proofreading	1	1404.3×	0.006	POLE
relaxation of skeletal muscle	1	1404.3×	0.006	KBTBD13
leading strand elongation	1	1053.2×	0.006	POLE
paraxial mesoderm formation	1	842.6×	0.006	EXOC4
nucleotide-excision repair, DNA gap filling	1	702.2×	0.006	POLE
obsolete vesicle tethering involved in exocytosis	1	468.1×	0.008	EXOC4
protein transmembrane transport	1	324.1×	0.010	EXOC4
base-excision repair, gap-filling	1	280.9×	0.010	POLE
DNA synthesis involved in DNA repair	1	234.1×	0.011	POLE
obsolete vesicle docking involved in exocytosis	1	168.5×	0.013	EXOC4
DNA-templated DNA replication	1	140.4×	0.014	POLE
Golgi to plasma membrane transport	1	140.4×	0.014	EXOC4
embryonic organ development	1	120.4×	0.015	POLE
membrane fission	1	102.8×	0.016	EXOC4
regulation of macroautophagy	1	73.9×	0.021	EXOC4
mitotic cytokinesis	1	64.8×	0.023	EXOC4
G1/S transition of mitotic cell cycle	1	50.1×	0.027	POLE
DNA replication	1	41.3×	0.032	POLE
exocytosis	1	38.0×	0.033	EXOC4
rRNA processing	1	35.4×	0.033	DDX51
mitotic cell cycle	1	33.4×	0.034	POLE
actin filament organization	1	29.7×	0.036	KBTBD13
chemical synaptic transmission	1	19.3×	0.053	EXOC4
protein ubiquitination	1	10.3×	0.093	KBTBD13

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 4

Druggability breadth: 2 of 4 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
POLE	0	0
DDX51	0	0
EXOC4	0	0
KBTBD13	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
EXOC4	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
POLE	2.7.7.7	DNA-directed DNA polymerase

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Drug repurposing candidates

0 approved/phased drugs hit cohort targets but don’t yet appear in disease-level clinical trials. Target-inhibition rationale is strongest for cancer driver genes; a bioactivity hit is a screening signal, not a treatment claim.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	POLE, DDX51, EXOC4, KBTBD13

Undrugged target profiles

4 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
POLE	0	—
DDX51	0	—
EXOC4	1	—
KBTBD13	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.